B细胞表达的TREM-2在体液免疫抗结核中的作用及分子机制研究

结核体液免疫水平和其预后相关，但调控机制仍不清楚。预实验结果显示，与健康人和潜伏感染者相比，活动性结核患者B细胞上髓样细胞诱发受体TREM-2的表达显著减少。进一步预实验发现，TREM-2敲除小鼠结核感染后荷菌量增加，抗体减少，抗体依赖细胞介导的细胞毒(ADCC)效应减弱，提示TREM-2可能通过增强ADCC介导结核菌清除。那么TREM-2增强ADCC的分子机制是什么？文献报道，结核不同感染状态抗体糖基化水平存在差异，抗体Fc段去岩藻糖基化可提高ADCC活性。我们发现，B细胞上的TREM-2可以结合Btk，抑制岩藻糖基转移酶FUT8表达。综上，我们提出科学假说：“TREM-2通过活化Btk促进B细胞活化和抗体Fc段岩藻糖基化水平，增强ADCC介导的抗结核免疫”。本项目拟通过体内外实验和临床样本检测，深入阐明TREM-2在结核体液免疫中的作用及分子机制，为探索新的结核治疗靶点提供理论依据。

The humoral immunity of tuberculosis is related to its prognosis, but the regulatory mechanism is still unclear. Pre-experimental results showed that compared with healthy people and latent TB infections, the expression of myeloid cell-induced receptor TREM-2 on B-cells in patients with active tuberculosis was significantly reduced. Further pre-experiments found that after TB infection in TREM-2 knockout mice, the bacterial load increased, the antibodies decreased, and antibody-dependent cell-mediated cytotoxicity (ADCC) effects weakened, suggesting that TREM-2 may mediate tuberculosis clearance by enhancing ADCC. So what is the molecular mechanism by which TREM-2 enhances ADCC? It has been reported in the literature that there are differences in antibody glycosylation levels in different infection states of tuberculosis. Defucosylation of the Fc segment of antibodies can increase ADCC activity. We found that TREM-2 on B cells can bind Btk and inhibit the expression of fucosyltransferase FUT8. In summary, we propose a scientific hypothesis: "TREM-2 promotes B-cell activation and fucosylation of the Fc region of antibodies by activating Btk, and enhances ADCC-mediated anti-tuberculosis immunity." This project intends to clarify the role and molecular mechanism of TREM-2 in humoral immunity of tuberculosis through in vivo and in vitro experiments and clinical sample detection, and provide theoretical basis for exploring new targets for tuberculosis treatment.